The application proposes a career development plan for Dr. Pietro Cottone, a pharmacologically trained post-doctoral fellow committed to a research career in understanding the molecular bases of food and drug addiction. The applicant will be mentored by Dr. George Koob in behavioral neuroscience methods and animal models of dependence and drug withdrawal and co-mentored by Dr. Eric Zorrilla in issues related to feeding, stress neurochemistry, and anxiety-like behavior and by Dr. Pietro Sanna in biochemical and neuroanatomical techniques. The project will be conducted at The Scripps Research Institute in the rich neuroscience community of San Diego. The proposal hypothesizes that neuroadaptations in CRF systems of the extended amygdala mediate negative affective consequences of palatable food withdrawal and thereby come to compel palatable food intake via a negative reinforcement mechanism. Studies use a novel animal model based on "intermittent, but extended, access to palatable food that shares conceptual underpinnings with drug dependence-models and which emphasizes the "dark side" of food addiction, an understudied, innovative area of research. Preliminary studies with the model found that consummatory and affective dependence on palatable food develop with intermittent access and suggest that palatable food may come to be eaten compulsively for acquired negative reinforcing properties, as has been proposed for abused drugs. Additional behavioral and electrophysiological preliminary studies suggest a key role for CRF1 receptor in the alterations observed during withdrawal from preferred food in this model. Specific Aims 1 and 2 combine sophisticated behavioral techniques (progressive ratio reinforcement schedules, intracranial self-stimulation, elevated plus maze) with complementary neuropharmacologic and brain site-specific lentiviral siRNA knockdown approaches to determine the role of CRF1 receptors in the hypophagia, motivational deficits, and anxiogenic-like behavior that is seen upon withdrawal from palatable food. Specific Aim 3 identifies molecular changes in mRNA and protein expression of CRF/CRF1 systems in discrete regions of the central extended amygdala that are observed during withdrawal from chronic, intermittent palatable food access. Relevance: The project seeks to define the role and potential therapeutic relevance of stress-related CRF systems on food addiction. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]